We have demonstrated that natural killing by human peripheral blood mononuclear cells is reversibly suppressed by monocytes or polymorphonuclear cells (PMN) when these cells are stimulated to release reactive metabolites of oxygen, particularly hydrogen peroxide. We propose to examine the mechanism and scope of this suppression, using highly purified cell populations. Our specific aims are to: (1) Determine whether RO act directly on natural killer (NK) cells or whether other cell populations are required. (2) Examine the cellular mechanism of suppression of natural killing by determining whether suppression is accompanied by changes in (a) the number of target-binding cells (TBC), (b) the efficiency of cytolysis by TBC or (c) the recycling of killing by NK cells. (3) Determine whether suppression of cytotoxicity is unique to NK cells or is also seen with other cytotoxic cell mechanisms, including antibody-dependent cellular-cytotoxicity and T-cell cytotoxicity. (4) Determine whether decreased levels of natural killing in patients with autoimmune diseases, such as systemic lupus erythematosus or Sjogren's syndrome, involves suppression of NK by monocytes through the release of RO. The regulation of natural killing by RO provides a well-defined model for examining the effects of RO on cell function. This mechanism for cell-cell regulation is likely to be most significant at sites of inflammation, where monocytes and PMN are stimulated to release RO.